Prostate cancer is the most common malignancy in men, and, after lung cancer, the second leading cause of death in men. There were an estimated 241,740 new cases in 2012 resulting in 28,170 deaths (www.cancer.gov). Most tumors are confined to the prostate, and most patients develop clinically insignificant prostate cancer, while other patients develop disseminated disease that is rapidly fatal.
Currently, about 30% of prostate cancer recurs after radical prostatectomy (RP). The identification of patients with a high recurrence risk is a challenge. The natural history of prostate carcinoma is extremely variable and rather unpredictable by existing methods (e.g., Gleason score). There is a need for effective predictors of tumor recurrence following surgery in order to determine whether a patient should be treated immediately with adjuvant therapy. Patients with tumors that are not biologically malignant would not benefit from such medical intervention. The foregoing, coupled with the significant morbidity associated with RP for apparently localized disease, and the high cost of RP, underscore the importance of discovering reliable molecular markers to predict the behavior of individual carcinomas.
Various markers and methods have been disclosed. For example, the measurement of the level of amplification of the HER-2/neu gene by fluorescent in situ hybridization (FISH) has been disclosed to be a method of determining the severity of prostate cancer (Int'l Pat. App. Pub. No. WO 1998/045479; “the '479 application”). In accordance with the method of the '479 application, a patient having five or more copies of Her-2/neu is treated aggressively. The determination of the presence of an amplified 8q24.1-24.2 chromosome band segment has been disclosed to be a method of diagnosing prostate cancer progression (U.S. Pat. No. 5,658,730). The determination of the loss of the 8p21-22 locus, a gain of chromosome 8, and an additional increase of the copy number of c-myc relative to the centromere copy number has been disclosed to be a method of prognosticating prostate cancer (U.S. Pat. No. 6,613,510). A gain of 8q24 (c-myc) and a loss of heterozygosity (LOH) of 8p21-22 (Bova et al., Cancer Res. 53: 3869-3873 (1993); and Kagan et al., Oncogene 11: 2121-2126 (1995); see, also, Emmert-Buck et al., Cancer Res. 55: 2959-2962 (1995), regarding allelic loss for 8p12-21) and 10q23 (PTEN) (Yoshimoto et al., Br. J. Cancer 97(5): 678-685 (Sep. 3, 2007; epub Aug. 14, 2007) also have been disclosed. Testing for the loss of heterozygosity at one or more loci on one or more of chromosomes 1-22 has been disclosed as a method of detecting a cell with a neoplastic or preneoplastic phenotype (U.S. Pat. App. Pub. No. 2003/0165895; “the '895 application”). The methods of the '895 application are disclosed as applicable to the detection of genetic changes relating to the progression of various cancers. Analysis of 20P1F12/TMPRSS2, such as in a method of identifying evidence of a neoplasm, has been disclosed as useful for the assessment of prostate cancer (U.S. Pat. No. 7,037,667). Detecting a fusion between a 5′ portion of TMPRSS2 and a 3′ portion of ERG, ETV1, ETV4 or FLI1 and the presence of a PCA3 nucleic acid molecule has been disclosed as another method of identifying or characterizing prostate cancer (U.S. Pat. No. 8,580,509; see, also, U.S. Pat. Nos. 8,211,645 and 7,718,369 and U.S. Pat. App. Pub. Nos. 2012/0295809). A method of predicting recurrence, progression, and metastatic potential of prostate cancer comprising detecting three or more biomarkers selected from FOXO1A, SOX9, CLNS1A, PTGDS, XPO1, LETMD1, RAD23B, ABCC3, APC, CHES1, EDNRA, FRZB, HSPG2, and TMPRSS:ETV1 is disclosed in U.S. Pat. App. Pub. No. 2011/0230361 and Int'l Pat. App. Pub. No. WO 2010/056993. Screening prostate cancer patients with ERG-activation or ERG-translocation in order to evaluate responsiveness to anti-ERG therapy is disclosed in Int'l Pat. App. Pub. No. WO 2008/023087. The detection of TMPRSS2:ERG fusions, duplications thereof, and interstitial deletions 5′ to ERG, along with Gleason score and PSA level, have been reported to enable stratification of patients with prostate cancer (Attard et al., Oncogene 27(3): 253-263 (January 2008); e-pub. Jul. 16, 2007). The detection of the overexpression of ERG, as well as the fusion of a 3′ portion of ERG with a 5′ portion of an androgen-regulated gene, such as TMPRSS2, NDRG1, SLC45A3 or PSA, has been disclosed for the early-stage diagnosis of prostate cancer (U.S. Pat. App. Pub. No. 2012/0220672; see, also, U.S. Pat. App. Pub. No. 2012/0039889 in re ERG:NDRG1 fusions). The use of HERPUD1:ERG and AX747630:ETV1 fusions in the identification of prostate cancer in a patient has been disclosed in U.S. Pat. App. Pub. No. 2012/0015839 (see, also, U.S. Pat. App. Pub. Nos. 2009/0239221 and 2009/0208937 for the use of other ERG and ETV1 gene fusions). The use of MIPOL1:ETV1 to detect prostate cancer is disclosed in U.S. Pat. App. Pub. No. 2011/0028336, whereas the use of ACSL3:ETS, such as ACSL3:ETV1, to diagnose a patient as having prostate cancer, as having aggressive prostate cancer, or as likely to develop prostate cancer and to assess whether a prostate tumor in a patient is suitable for anti-androgen therapy is disclosed in Int'l Pat. App. Pub. No. WO 2009/0144460 (“the '460 application”). Also disclosed in the '460 application is the use of an ETV1 fusion to assess Gleason score and/or clinical stage of prostate cancer and determine prognosis for prostate cancer. The detection of an ARG-ETS gene fusion, such as ARG:ERG and ARG:ETV1, has been disclosed as a method of screening for a prostate neoplasm (Canadian Pat. App. No. 2814598). U.S. Pat. App. Pub. No. 2012/0214684 discloses the use of a marker selected from OCT3/4, Nanong, Sox2, c-Myc, Klf4, Keratin 8, and uPAR in the detection of a neoplasia, such as prostate carcinoma, the characterization of the aggressiveness of prostate cancer, the monitoring of the effectiveness of therapy, and the selection of a treatment. Methods of assessing the progression of cancer and diagnosing carcinoma, melanoma, colon cancer, and prostate cancer by examining the level of an expression product of a gene selected from a group, which includes ETV1, among other methods, are disclosed in U.S. Pat. App. Pub. No. 2007/0237770. The measurement of at least two cell-cycle genes, such as AURKA, alone or in further combination with PTEN, has been disclosed in the classification of cancer, such as prostate cancer, in U.S. Pat. App. Pub. No. 2012/0041274. The use of MYC RNA, alone or in further combination with PTEN RNA, has been disclosed for the assessment of survivability in U.S. Pat. App. Pub. No. 2012/0009581. The determination of survival (e.g., diagnosis, prognosis, prediction of response, and/or relative survival rate) for a disease, such as cancer (e.g., prostate cancer), by quantification of at least two proteins, such as PTEN, is disclosed in U.S. Pat. App. Pub. No. 2011/0306514. The use of PCA3 and at least one other marker selected from a group, which includes TMPRSS2:ERG, to detect prostate cancer is disclosed in Int'l Pat. App. Pub. No. WO 2009/0140741. A method of diagnosing prostate cancer progression, or prostate cancer recurrence, comprising determining the presence of an amplified 8q24 chromosomal band segment is disclosed in Int'l Pat. App. Pub. No. 1996/020288. The use of a hybridization composition, which comprises a probe, a polar aprotic solvent other than DMSO, less than 10% formamide, and hybridization solution to detect a condition, such as cancer (e.g., prostate cancer), is disclosed in U.S. Pat. App. Pub. No. 2011/0281263. The probe in the hybridization composition can detect, for example, c-MYC, MYCN, PTEN, MDM2, FGFR1, AURKA, CEP8 or CEP10, among others. A method of characterizing prostate tissue by determining the levels of expression of a set of genes selected from ABP280 (FLNA), AMACR, AR, BM28, BUB3, CaMKK, CASPASE3, CDK7, DYNAMIN, E2F1, E-CADHERIN, EXPORTIN, EZH2, FAS, GAS7, GS28, ICBP90, ITGA5, JAGGED1, JAM1, KANADAPTIN, KLF6, KRIP1, LAP2, MCAM, MIB1 (MK167), MTA1, MUC1, MYSOIN-VI, P27, P63, PAXILLIN, PLCLN, PSA (KLK3), BAP27, RBBP, RIN1, SAPKα, TPD52, XIAP, and ZAG is disclosed in U.S. Pat. App. Pub. No. 2006/0234259; the method reportedly can involve prognosis, such as predicting prostate disease progression. Measurement of the level of two or more determinants selected from a list of 372 determinants in a method of assessing risk of recurrence of cancer or development of metastasis is disclosed in U.S. Pat. App. Pub. No. 2011/0265197; the method can reportedly involve measurement of a standard parameter, such as Gleason score for prostate cancer. The measurement of the expression level of ERG, alone or in further combination with the expression level of AMACR, in the diagnosis or prognosis of prostate cancer also has been disclosed in U.S. Pat. App. No. 2013/029860 (see, also, U.S. Pat. App. Pub. No. 2010/0215638 for the use of other ERG-associated genes in the screening of prostate cancer and the like). The detection of one or more biomarkers (e.g., RNA or protein) selected from a group consisting of CSPG2, WNT10B, E2F3, CDKN2A, TYMS, TGFB3, ALOX12, CD44, LAF4, CTNNA1, XPO1, PTGDAS, SOX9, RELA, EPB49, SIM2, EDNRA, RAD23B, FBP1, TNFRSF1A, CCNG2, LETMD1, NOTCH3, ETV1, BID, SIM2, ANXA1, BCL2, FOXO1A, CLNS1A, PTGDS, XPO1, LETMD1, RAD23B, ABCC3, APC, CHES1, EDNRA, FRZB, HSPG2, TMPRSS2:ETV1, CSPG2, CDKN2A, and others has been disclosed for the prediction of the recurrence, progression and metastatic potential of cancer (see U.S. Pat. App. Pub. No. 2013/0005837). The combination of FGFR1, PMP22, and CDKN1A has been reported to predict accurately the outcome of low Gleason-score tumors (Irshad et al., Sci. Transl. Med. 5(202): 202 (Sep. 11, 2013)). A method of diagnosing cancer, such as prostate cancer, comprising detecting differential expression of a gene selected from a group of 73 genes, which includes FGFR1, is disclosed in Canadian Pat. App. No. 2604844 (see, also, European Pat. App. No. 2083088). The use of PCA3 and a prostate-specific marker (e.g., NKX3.1), such as a ratio thereof, to prognose, assess tumor volume, monitor, determine risk of progression, and stage prostate cancer also has been disclosed (U.S. Pat. No. 8,257,924). The use of two or more genes selected from PSA/KLK3, PMEPA1, NKX3.1, ODC1, AMD1, and ERG to prognose prostate cancer, or evaluate androgen receptor signaling, such as by detection or measurement of expression, is disclosed in Canadian Pat. App. No. 2719172. The use of at least two molecular markers selected from her2/neu, p16, p53, Ki67, MN, mdm-2, bcl-2, and EGFR in an automatable method for identifying cancer cells and their precursor cells in a cell/tissue sample, such as a sample obtained from a prostate, is disclosed in U.S. Pat. No. 7,452,727. A method of prognosticating prostate cancer comprising determining a hybridization pattern of a set of chromosomal probes consisting of probes for 8p21-22, chromosome 8, and C-MYC is disclosed in U.S. Pat. No. 6,613,510. The use of antibodies to ERG, TFF3 and a high molecular weight cytokeratin to detect prostate cancer has been disclosed, including complete concordance between ERG expression by IHC and ERG gene status (i.e., rearrangement) by FISH, although no association between ERG/TFF3 expression and parameters, such as age, PSA, Gleason score, tumor stage, and biochemical recurrence, was observed (Int'l Pat. App. Pub. No. WO 2013/0173463). The use of expression levels of c-Myc, Ha-Ras, NeuT, and/or c-Src in the diagnosis of prostate cancer, the classification of a prostate cancer/tumor into a distinct prostate cancer subclass, and, in further combination with ErbB2, the stratification of a patient with a tumor, such as a prostate tumor, for clinical trial is disclosed in U.S. Pat. App. Pub. No. 2014/0109245. The use of two or more markers selected from TARDBP, TLN1, PARK7, ISPI1, CALD1, p73, PTEN, PXN, PEX10, KL3, DBN1, NFAT1, B-Tubulin, SOS1, HSF4, TOP1, HSPA1A, ACID2, STAT2, p53, CHD3 CASP8, STX6, AR, GAPDHS, cyclin D1, and CCNA2 to evaluate diagnostically a subject for prostate cancer is disclosed in U.S. Pat. App. Pub. No. 2014/0066325. A method of subtyping prostate cancer (e.g., risk of developing lethal neuroendocrine prostate cancer (NEPC)) involving the determination of the overexpression/amplification of AURKA and/or MYCN, alone or in further combination with ERG rearrangement, is disclosed in U.S. Pat. App. Pub. No. 2014/037647. The use of five or more markers selected from HOXA7, AURKA, NEK2, FOXM1B, CCNB1, CEP55, CENPA, DNMT3B, DNMT1, HELLS, MAPK8, BMI1, ITGB1, IVL, and CTNNB1 to diagnose, or monitor progression of, cancer, such as prostate cancer, is disclosed in Int'l Pat. App. Pub. No. 2012/013931. The detection of a break in the sequence of human chromosome 12q24 at the SMRT gene locus using FISH has been disclosed as a method of determining the likelihood of prostate cancer metastasis (U.S. Pat. No. 7,425,414). The determination of the level of a constituent, such as PTEN RNA, has been disclosed in the evaluation of prostate cancer, the assessment/monitoring of response to therapy in a patient with prostate cancer, and the monitoring of the progression of prostate cancer (Int'l Pat. App. Pub. No. WO 2008/121132). The detection of increased expression of ERG and decreased expression of PTEN, such as by detecting mRNA, protein, or alteration(s) in genomic sequence(s) (e.g., amplification, deletion, or fusion), to determine the aggressiveness of prostate cancer or that the prostate cancer has penetrated, or will likely penetrate, the prostatic capsule is disclosed in U.S. Pat. App. Pub. No. 2013/0196866 as is the detection of decreased expression of PTEN to determine recurrence of prostate cancer. The use of (i) MYC, PTEN, CEP8 and CEP7, (ii) MYC, LPL, PTEN, and CEP8, or (iii) MYC and CEP8 in the detection of prostate cancer is disclosed in U.S. Pat. App. Pub. No. 2013/0171638. The detection of the over-expression of PITX2 has been disclosed as a method for diagnosing the presence or risk of prostate cancer and, in combination with at least one other factor, such as PSA or Gleason grade, as a method for prognosticating prostate cancer (Int'l Pat. App. Pub. No. WO 2010/099577). The identification of an increased level of a nucleic acid or polypeptide selected from OCT3/4, Nanog, Sox2, c-myc, KIf4, keratin 8, and uPAR has been disclosed as a method of identifying a prostate carcinoma, a method of characterizing the aggressiveness of a prostate cancer, a method of identifying a propensity for developing metastatic prostate cancer, and other methods (Int'l Pat. App. Pub. No. 2011/037643). A method of predicting the likelihood of recurrence of cancer following treatment in a patient comprising determining the expression level of p27, or its expression product, is disclosed in U.S. Pat. App. Pub. No. 2003/0225528, whereas a method for determining the aggressiveness of prostate carcinoma comprising detecting p27 protein is disclosed in Int'l Pat. App. Pub. No. WO 2000/077258, which also discloses a method for determining the rate of proliferation of prostate cancer comprising detecting MDM2 expression (see, also, Canadian Pat. App. No. 2,375,228). A method of detecting a cell with a neoplastic or preneoplastic phenotype comprising testing a sample for loss of heterozygosity (LOH) at one or more loci on one or more chromosomes, such as those which are related to progression from preneoplasia to invasive carcinoma, is disclosed in U.S. Pat. App. Pub. No. 2003/0165895. A method of evaluating prostate cancer comprising quantitatively measuring at least one RNA (e.g., MYC) under repeatable conditions such that the measurement distinguishes prostate cancer from melanoma, lung cancer, and colon cancer with at least 75% accuracy is disclosed in U.S. Pat. App. Pub. No. 20111/097717 (see, also, U.S. Pat. App. Pub. No. 2010/0233691). A panel of isolated cancer biomarkers consisting of DUSP6, SPRY2 and one or more biomarkers selected from a group of approximately 33 genes, which includes ETV1, is disclosed in U.S. Pat. App. Pub. No. 2008/0131885.
In view of the foregoing, there remains a need for more reliable and informative prognostic methods in the management of prostate cancer. The present disclosure seeks to provide sets of markers, as well as methods of use and kits comprising the sets of markers, for the assessment of the progression of prostate cancer. This and other objects and advantages, as well as inventive features, will become apparent from the detailed description provided herein.